Local application of bacteria improves safety of Salmonella -mediated tumor therapy and retains advantages of systemic infection

// Dino Kocijancic 1, * , Sebastian Felgner 1, 2, * , Tim Schauer 1 , Michael Frahm 1 , Ulrike Heise 3 , Kurt Zimmermann 4 , Marc Erhardt 2 and Siegfried Weiss 1, 5 1 Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, Germany 2 Infection Biology of Salmonella, Helmholtz Center for Infection Research, Braunschweig, Germany 3 Mouse-Pathology Service Unit, Helmholtz Center for Infection Research, Braunschweig, Germany 4 Symbio Gruppe GmbH & Co KG, Herborn, Germany 5 Institute of Immunology, Medical School Hannover, Hannover, Germany * These authors have contributed equally to this work Correspondence to: Dino Kocijancic, email: dino.kocijancic@helmholtz-hzi.de Keywords: Intra-tumoral injection, Salmonella, E. coli, bacteria mediated tumor therapy, murine tumor model Received: October 29, 2016      Accepted: May 05, 2017      Published: June 07, 2017 ABSTRACT Cancer is a devastating disease and a large socio-economic burden. Novel therapeutic solutions are on the rise, although a cure remains elusive. Application of microorganisms represents an ancient therapeutic strategy, lately revoked and refined via simultaneous attenuation and amelioration of pathogenic properties. Salmonella Typhimurium has prevailed in preclinical development. Yet, using virulent strains for systemic treatment might cause severe side effects. In the present study, we highlight a modified strain based on Salmonella Typhimurium UK-1 expressing hexa-acylated Lipid A. We corroborate improved anti-tumor properties of this strain and investigate to which extent an intra-tumoral (i.t.) route of infection could help improve safety and retain advantages of systemic intravenous (i.v.) application. Our results show that i.t. infection exhibits therapeutic efficacy against CT26 and F1.A11 tumors similar to a systemic route of inoculation. Moreover, i.t. application allows extensive dose titration without compromising tumor colonization. Adverse colonization of healthy organs was generally reduced via i.t. infection and accompanied by less body weight loss of the murine host. Despite local application, adjuvanticity remained, and a CT26-specific CD8 + T cell response was effectively stimulated. Most interestingly, also secondary tumors could be targeted with this strategy, thereby extending the unique tumor targeting ability of Salmonella . The i.t. route of inoculation may reap the benefits of systemic infection and aid in safety assurance while directing potency of an oncolytic vector to where it is most needed, namely the primary tumor.